Monoclonal Gammopathy of Undetermined Significance
R. A. Kyle
S UMMA R Y. Monoclonal gammopathy of undetermined signiiicance (MGUS) accounted for 56% of the 1026 patients with a mouoclonal plasma cell disorder seen at the Mayo Clinic duriug 1992. Approximately 3% of persons older than 70 years and 1% of those older than 50 years had MGUS. In a series of 241 Mayo Clinic patients with a serum M-protein but no evidence of multiple myeloma, macro- p&nary amyloidosis, lymphoma, or related disorders, followed up for 20 to 35 years (median, 22 years), the condition of 19% remained stable. Ten percent had an increase in the serum M-protein to 3.0 g/dL or more but did not require chemotherapy, whereas 47% died of unrelated causes. 59 of the 241 patients (24.5%) developed a serious disease dmkg the median follow- up period of 22 years: multiple myeloma in 39 patients, primary amyloidosis in 8, Walden&&ns macroglob&emia io 7, and other malignant lymphoproliferative disorders in 5. The actuarial rate of malignant transformation was 17% at 10 years and 33% at 20 years. The median interval from diagnosis of MGUS to the diagnosis of serious disease was 8.5 to 10.5 years. No single factor can difterentiate a patient with benign monoclonal gammopathy from one in whom a malignant plasma cell disorder will subsequently develop. Therefore, the serum M-protein must be measured and a clinical evaluation conducted periodically.
The term monoclonal gammopathy of undetermined significance (MGUS) indicates the presence of a monoclonal (M-) protein in persons without evidence of multiple myeloma, WaldenstrBms macroglobuline- mia, primary amyloidosis, or related disorders. The term benign monoclonal gammopathy is misleading because one does not know at the time of diagnosis whether the monoclonal gammopathy will remain stable or will develop into symptomatic multiple myeloma, Waldenstriims macroglobulinemia or related lymphoproliferative disorders, or primary amyloidosis.
During 1992, 1026 patients with a monoclonal plasma cell disorder were seen at the Mayo Clinic (Fig. 1). MGUS was the most common disorder,
Robert A. Kyle, MD, Consultant, Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation; Professor of Medicine and of Laboratory Medicine, Mayo Medical School; Rochester, Minnesota 55905, USA.
affecting 56% (578 patients). We have defined MGUS as a serum M-protein value less than 3 g/dL, fewer than 10% plasma cells in the bone marrow, none or a small amount of M-protein in the urine (Bence Jones proteinuria), absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency, and, most importantly, stability of the M-protein and failure of development of other abnormalities during long-term follow-up.
The frequency of monoclonal gammopathies with- out evidence of multiple myeloma, Waldenstrdms macroglobulinemia, primary amyloidosis, or related diseases is approximately 3% in patients older than 70 years and about 1% in those older than 50 years. An M-protein was found in 64 (0.9%) of 6995 persons older than 25 years in a mass health control study in Sweden. An M-protein was recognized in 0.7% of 102000 serum samples from a general hospital in Italy and in 1.2% of 73 630 hospitalized
Bbod Reviews (1994) 8, 135-141 Q 1994 Longman Group Ltd
136 MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
Amyloidosis (AL) (106)
Fig. 1 Patients with monoclonal plasma cell disorders seen at Mayo Clinic in 1992. CLL, chronic lymphocytic leukemia; Macro, macroglobulinemia; MGUS, monoclonal gammopathy of undetermined significance; SMM, smoldering multiple myeloma.
patients in the United States.3 In Finistere, France, the frequency of serum M-proteins was 1.1% in 30 279 adults.4 The frequency of M-proteins increases with age. In persons older than 80 years, the frequency of serum M-proteins, as assessed by cellulose acetate electrophoresis, ranges from 4.1% to 5 2O/o 1*4-6 In a study using high-resolution agarose . . gel electrophoresis and immunofixation, the fre- quency of M-proteins in subjects 62 to 80 years was 6%, whereas 14% of those older than 90 years had a serum M-component. In contrast, the presence of an M-protein is rare in persons younger than 50 years. Axelsson et a1.l found M-components in only 0.15% (5 of 3321) of persons younger than 50 years, and Saleun et a1.4 noted an M-protein in 0.2% (26 of 12032). In these two series, no M-proteins were recognized in persons younger than 30 years. The incidence of M-components in the African-American population is higher than in whites.8,9
Thus, the prevalence of MGUS is considerable. It is of particular importance to know whether the disorder will remain stable and benign or will progress to multiple myeloma or related disorders requiring chemotherapy.
not directly related to the monoclonal gammopathy. Anemia, leukopenia, leukocytosis, thrombocyto- penia, and thrombocytosis were uncommon, and when present they were unrelated to the monoclonal gammopathy. The initial amount of the M-protein ranged from 0.3 to 3.2 g/dL (median, 1.7 g/dL). The heavy-chain type was IgG in 73%, IgA in ll%, and IgM in 14%. The type of light chain was K in 62% and h in 38%. A biclonal gammopathy was found in 5 patients (2.1%). 29% had a decrease in uninvolved (background) immunoglobulins. Nine patients had Bence Jones proteinuria at or before the recognition of the serum M-protein, but the amount of urinary light chain was more than 1 g/24 h in only 3 patients. The median value of bone marrow plasma cells in the 109 patients in whom bone marrow aspiration was performed at diagnosis of MGUS was 3% (range, l-10%). Diseases associated with the M-protein are listed in Table 1. There was no apparent relationship between any of the disorders and the M-protein.
After 20 to 35 years of follow-up (median, 22
Table 1 Monoclonal gammopathy of undetermined significance (Mayo series): diseases associated with serum monoclonal protein at time of diagnosis
Mayo Clinic Study Disease
A series of 241 Mayo Clinic patients with a serum M-protein but no evidence of multiple myeloma, Waldenstroms macroglobulinemia, primary amy- loidosis, lymphoma, or related disorders have been followed for 20 to 35 years and the data are periodically updated. lo-l2 The median age was 64 years; 4% were younger than 40 years, and 33% were 70 years or older. 58% were male.
The liver was palpable in 15% of patients, and the spleen was palpable in 4%, but these findings were
None 62 26 Cardiac and cerebrovascular 31 13 Inflammatory 26 11 Malignant 16 7 Connective tissue 14 6 Neurologic 15 6 Benign tumor 8 3 Hematologic 9 3.5 Endocrine 9 3.5 Miscellaneous 51 Total 241 1:
From Kyle. lo By permission of Reed Publishing USA.
No. cases %
BLOOD REVIEWS 137
years), the 241 patients were classified into four groups (Table 2). The number of patients in whom the M-component remained stable and who were classified as benign had decreased to 46 ( 19%) (group 1). However, they are still at risk for develop- ment of malignancy. The patient with longest follow- up was found to have an IgM M-protein 37 years ago and at last follow-up was still alive and well at the age of 93 years. The M-component disappeared in two patients. Group 2 included 23 patients in whom the serum M-protein increased to 3.0 g/dL or more, but they did not require chemotherapy for multiple myeloma, Waldenstroms macroglobuline- mia, or primary amyloidosis. Five of these patients are still living and thus at risk for development of symptomatic disease. The pattern of increase was gradual in most patients, but 3 patients had a sudden increase without development of symptomatic malig- nancy. The median interval from the detection of the M-protein to an increase to 3.0 g/dL was 9 years, and the median duration of follow-up after reaching this increase was 6 years. Almost one half of the patients died from unrelated diseases without devel- opment of a malignant plasma cell or lymphoprolifer- ative process and can be considered as having a benign monoclonal gammopathy (group 3).
In one fourth of the patients (59 of the 241, 24.5%), malignant transformation developed during the median follow-up of 22 years (group 4). This consisted of multiple myeloma (39 cases), primary amyloidosis (8 cases), Waldenstroms macroglobuli- nemia (7 cases), and other malignant lymphopro- liferative disorders (5 cases). The actuarial rate of malignant transformation was 17% at 10 years and 33% at 20 years (Fig. 2). The actuarial risk of development of a malignant gammopathy among 202 patients with IgG or IgA M-protein was 15% at 10 years and 30% at 20 years, whereas the actuarial risk among the 34 patients with an IgM M-protein was 19% and 48% at 10 and 20 years, respectively. As shown in Figure 3, the risk of malignant transfor-
Table 2 Course of 241 patients with monoclonal gammopathy of undetermined signifkance
No. of patients at follow-up (median, 22 yr)
Group Description No. %
1 No substantial increase of serum 46 19 or urine monoclonal protein @en&
2 Monoclonal protein 2 3.0 g/dL 23 10 but no symptomatic myeloma or related disease
3 Died of unrelated causes 113 47 4 Development of myeloma, 59 24
macroglobulinemia, amyloidosis, or related disease
Total 241 100
From Kyle. By permission of Mayo Foundation for Medical Education and Research
mation was not significantly different depending on the type of M-protein.
The mode of development of multiple myeloma after MGUS was variable. In 11 patients, the serum M-protein remained stable for 4 to 18 years (median, 8 years) and then gradually increased to symptomatic multiple myeloma during a l- to 4-year period (median, 3 years). In 7 patien